This invention relates generally to human immunodeficiency virus (HIV) and, more specifically to compounds that are prophylactic against transmission of and/or effectively treat HIV infection.
Prevention of human immunodeficiency virus (HIV) transmission can be realized by approaches that interrupt the early phase of retrovirus infection, before provirus formation. One early event, HIV entry into target cells, involves the viral envelope glycoproteins, gp120 and gp41, and host cell receptors, CD4 and the chemokine receptors (either CCR5 or CXCR4). Binding to CD4 induces conformational changes in the exterior envelope glycoprotein gp120 that allow CCR5/CXCR4 engagement and that expose elements of the gp41 transmembrane glycoprotein. Further conformational changes in gp41 lead to fusion of the viral and host cell membranes, allowing virus entry. Each of these steps represents a potential target for intervention.
To evade host antibody responses, HIV has evolved envelope glycoproteins with surface variability, dense glycosylation and conformational flexibility. The unliganded HIV gp120 glycoprotein is unusually flexible and partially unstructured; binding CD4 locks gp120 into a rigid conformation. This binding event is characterized by an unusually large and favorable enthalpy change that is partially countered by a large unfavorable entropy change. High-resolution structures of CD4-bound HIV gp120 have provided insights into these conformational transitions. The conserved gp120 core consists of an inner domain that interacts with gp41, an outer domain with a heavily glycosylated surface, and a bridging sheet that connects these two domains. On the unliganded HIV gp120, the inner and outer gp120 domains are thought to move with respect to each other, with the bridging sheet assuming a conformation different from that seen in the CD4-bound state.
CD4 primarily contacts the gp120 outer domain and bridging sheet. CD4 binding creates a 153-Å cavity (“the Phe 43 cavity”) at the interface between gp120 and CD4; the Phe 43 cavity is bounded by highly conserved residues from all three gp120 domains and by a single CD4 residue, Phe 43. The contacts made by phenylalanine 43 and arginine 59 of CD4 with gp120 residues in the vestibule of this virtual pocket contribute significantly to gp120-CD4 affinity. Thus, the Phe 43 cavity has been indicated as a desirable target for compounds that could disrupt gp120-CD4 interactions.
It would therefore be beneficial to develop compounds that are capable of targeting the Phe 43 pocket. The present invention satisfies this need and provides related advantages as well.